Hypolipidemic benzothiazepine compounds

ABSTRACT

The invention is concerned with novel hypolipidemic compounds of formula (I),                    
     wherein R 1  is H or methyl, and salts, solvates or physiologically functional derivatives thereof, with processes and novel intermediates for their preparation, pharmaceutical compositions containing them and with their use in medicine, particularly in the prophylaxis and treatment of hyperlipidemic conditions and associated diseases, such as atherosclerosis.

This application is a Rule 371 Application of PCT/EP99/00021, filed Jan.7, 1999.

The present invention is concerned with new hypolipidemic compounds,with processes and novel intermediates for their preparation, withpharmaceutical compositions containing them and with their use inmedicine, particularly in the prophylaxis and treatment ofhyperlipidemic conditions and associated conditions such asatherosclerosis.

Hyperlipidemic conditions are often associated with elevated plasmaconcentrations of low density lipoprotein (LDL) cholesterol. Suchconcentrations can be reduced by decreasing the absorption of bile acidsfrom the intestine. One method by which this may be achieved is toinhibit the bile acid active uptake system in the terminal ileum. Suchinhibition stimulates the conversion of cholesterol to bile acid by theliver and the resulting increase in demand for cholesterol produces acorresponding increase in the rate of clearance of LDL cholesterol fromthe blood plasma or serum.

The compounds of the present invention reduce the plasma or serumconcentrations of LDL cholesterol and in consequence are particularlyuseful as hypolipidemic agents. By decreasing the concentrations ofcholesterol and cholesterol ester in the plasma, the compounds of thepresent invention retard the build-up of atherosclerotic lesions andreduce the incidence of coronary heart disease-related events. Thelatter are defined as cardiac events associated with increasedconcentrations of cholesterol and cholesterol ester in the plasma orserum.

International Patent Application No. PCT/GB/9300328 describes1,4-benzothiazepine compounds which have hypolipidemic activity.International Patent Application No. PCT/GB95/02700 (published asWO/9616051) describes 1,5-benzothiazepine compounds which also havehypolipidemic activity. A group of substituted 1,5-benzothiazepinecompounds has been discovered which have surprising hypolipidemicactivity over those specifically disclosed in the prior art.

Accordingly, the present invention provides a compound of formula (I)

wherein

R¹ is H or methyl; or a salt, solvate or physiologically functionalderivative thereof.

Preferably R¹ is hydrogen.

Suitable compounds of formula (I) are selected from:

(±)-2,3,4,5-Tetrahydro-3-ethyl-3-butyl-5-phenyl-7-chloro-8-hydroxy-1,5-benzothiazepine-1,1-dioxide;

(3S)-2,3,4,5-Tetrahydro-3-ethyl-3-butyl-5-phenyl-7-chloro-8-hydroxy-1,5-benzothiazepine-1,1-dioxide;and

(±)-2,3,4,5-Tetrahydro-3-ethyl-3-butyl-5-phenyl-7-chloro-8-methoxy-1,5-benzothiazepine-1,1-dioxide;or a salt, solvate or physiologically functional derivative thereof.

Pharmaceutically acceptable salts are particularly suitable for medicalapplications because of their greater aqueous solubility relative to theparent, i.e., basic, compounds. Such salts must clearly have apharmaceutically acceptable anion or cation. Suitable pharmaceuticallyacceptable acid addition salts of the compounds of the present inventioninclude those derived from inorganic acids, such as hydrochloric,hydrobromic, phosphoric, metaphosphoric, nitric, sulphonic and sulphuricacids, and organic acids, such as acetic, benzenesulphonic, benzoic,citric, ethanesulphonic, fumaric, gluconic, glycollic, isothionic,lactic, lactobionic, maleic, malic, methanesulphonic, succinic,p-toluenesulphonic, tartaric and trifluoroacetic acids. The chloridesalt is particularly preferred for medical purposes. Suitablepharmaceutically acceptable base salts include ammonium salts, alkalimetal salts, such as sodium and potassium salts, and alkaline earthsalts, such as magnesium and calcium salts.

Salts having a non-pharmaceutically acceptable anion are within thescope of the invention as useful intermediates for the preparation orpurification of pharmaceutically acceptable salts and/or for use innon-therapeutic, for example, in vitro, applications.

Any references to “compound(s) of formula (I)”, “compounds of thepresent invention”, “compounds according to the invention” etc., referto compound(s) of formula (I) as described above or their salts,solvates or physiologically functional derivatives as defined herein.

The term “physiologically functional derivative” as used herein refersto any physiologically acceptable derivative of a compound of thepresent invention, for example, an ester, which upon administration to amammal, such as a human, is capable of providing (directly orindirectly) such a compound or an active metabolite thereof. Suchderivatives are clear to those skilled in the art, without undueexperimentation, and with reference to the teaching of Burger'sMedicinal Chemistry And Drug Discovery, 5th Edition, Vol 1: PrinciplesAnd Practice.

Physiologically functional derivatives, which upon administration to amammal, such as a human, is capable of providing (directly orindirectly) a compound of the invention or an active metabolite thereof,are commonly referred to as prodrugs. These prodrugs may or may not beactive in their own right. Suitably, prodrugs of the present inventionare formed at position R¹ to give C₁₋₆ ester or C₁₋₆ alkoxy groups.

Active metabolites are those which may be generated in vivo by themetabolism of the compounds of the present invention and include, forexample, glucuronides.

The compounds of the present invention can also exist in differentpolymorphic forms, for example, amorphous and crystalline polymorphicforms. All polymorphic forms of the compounds of the present inventionare within the scope of the invention and are a further aspect thereof.

The compounds of formula (I) are in forms wherein the carbon center—C(Et)(n-Bu)— is chiral. The present invention includes within its scopeeach possible optical isomer substantially free, i.e. as associated withless than 5%, of any other optical isomer(s), and mixtures of one ormore optical isomers in any proportions, including racemic mixtures. The(S)-isomer is preferred.

According to further aspects of the invention, there are also provided:

(a) the compounds of formula (I) and pharmaceutically acceptable salts,solvates and physiologically functional derivatives thereof for use astherapeutic agents, particularly in the prophylaxis and treatment ofclinical conditions for which a bile acid uptake inhibitor is indicated,for example, a hyperlipidemic condition, and associated diseases such asatherosclerosis;

(b) pharmaceutical compositions comprising a compound of formula (I) orone of its pharmaceutically acceptable salts, solvates, orphysiologically functional derivatives, at least one pharmaceuticallyacceptable carrier and, optionally, one or more other physiologicallyactive agents;

(c) the use of a compound of formula (I) or of a pharmaceuticallyacceptable salt, solvate, or physiologically functional derivativethereof in the manufacture of a medicament for the prophylaxis ortreatment of a clinical condition for which a bile acid uptake inhibitoris indicated, for example, a hyperlipidemic condition, and associateddiseases such as atherosclerosis;

(d) a method of inhibiting the absorption of bile acids from theintestine of a mammal, such as a human, which comprises administering aneffective bile acid absorption inhibiting amount of a compound offormula (I) or of a pharmaceutically acceptable salt, solvate, orphysiologically functional derivative thereof to the mammal;

(e) a method of reducing the blood plasma or serum concentrations of LDLcholesterol in a mammal, such as a human, which comprises administeringan effective cholesterol reducing amount of a compound of formula (I) orof a pharmaceutically acceptable salt, solvate, or physiologicallyfunctional derivative thereof to the mammal;

(f) a method of reducing the concentrations of cholesterol andcholesterol ester in the blood plasma or serum of a mammal, such as ahuman, which comprises administering an effective cholesterol andcholesterol ester reducing amount of a compound of formula (I) or of apharmaceutically acceptable salt, solvate, or physiologically functionalderivative thereof to the mammal;

(g) a method of increasing the fecal excretion of bile acids in amammal, such as a human, which comprises administering an effective bileacid fecal excretion increasing amount of a compound of formula (I) orof a pharmaceutically acceptable salt, solvate, or physiologicallyfunctional derivative thereof to the mammal;

(h) a method for the prophylaxis or treatment of a clinical condition ina mammal, such as a human, for which a bile acid uptake inhibitor isindicated, for example, a hyperlipidemic condition, and associateddiseases such as atherosclerosis, which comprises administering atherapeutically effective amount of a compound of the formula (I) or ofa pharmaceutically acceptable salt, solvate, or physiologicallyfunctional derivative thereof to the mammal;

(i) a method of reducing the incidence of coronary heart disease-relatedevents in a mammal, such as a human, which comprises administering aneffective coronary heart disease-related events reducing amount of acompound of formula (I) or of a pharmaceutically acceptable salt,solvate, or physiologically functional derivative thereof;

(j) a method of reducing the concentration of cholesterol in the bloodplasma or serum of a mammal, such as a human, which comprisesadministering an effective cholesterol reducing amount of a compound offormula (I);

(k) processes for the preparation of compounds of formula (I) (includingsalts, solvates and physiologically functional derivatives thereof asdefined herein); and

(l) novel chemical intermediates in the preparation of compounds offormula (I).

The compounds of the present invention may be administered conjunctivelywith other physiologically active agents, including hypolipidemic agentssuch as bile acid sequestering agents, fibric acid derivatives, orHMG-CoA reductase inhibitors (competitive inhibitors of3-hydroxy-3-methylglutaryl-coenzyme A reductase), for example statins,such as pravastatin, lovastatin, fluvastatin, or simvastatin.

The amount of a compound of formula (I) which is required to achieve thedesired biological effect will, of course, depend on a number offactors, for example, the specific compound chosen, the use for which itis intended, the mode of administration and the clinical condition ofthe recipient. In general, a daily dose is in the range of from 0.001 mgto 100 mg (typically from 0.01 mg to 50 mg) per day per kilogrambodyweight, for example, 0.01-10 mg/kg/day. Thus, orally administrableunit dose formulations, such as tablets or capsules, may contain, forexample, from 0.1 to 100 mg, typically from 0.1 to 10 mg, preferably 0.1to 5 mg. In the case of pharmaceutically acceptable salts, the weightsindicated above refer to the weight of the benzothiazepine ion derivedfrom the salt.

For the prophylaxis or treatment of the conditions referred to above,the compounds of formula (I) can be used as the compound per se, but arepreferably presented with an acceptable carrier in the form of apharmaceutical composition. The carrier must, of course, be acceptablein the sense of being compatible with the other ingredients of thecomposition and must not be deleterious to the recipient. The carriercan be a solid or a liquid, or both, and is preferably formulated withthe compound as a unit-dose composition, for example, a tablet, whichcan contain from 0.05% to 95% by weight of the active compound. Otherpharmacologically active substances can also be present including othercompounds of formula (I). The pharmaceutical compositions of theinvention can be prepared by any of the well known techniques ofpharmacy consisting essentially of admixing the components.

When the compound of formula (I) is used in combination with one or moreother physiologically active agents as described hereinbefore, theamount of the other physiologically active agents required to achievethe desired biological effect will also depend on a number of factors.The specific dose and dosing schedule will be readily determinable bythose skilled in the art. In general, the dose utilized will be the doseapproved for medical use in humans.

Pharmaceutical compositions according to the present invention includethose suitable for oral, rectal, topical, buccal (e.g. sub-lingual) andparenteral (e.g. subcutaneous, intramuscular, intradermal, orintravenous) administration, although the most suitable route in anygiven case will depend on the nature and severity of the condition beingtreated and on the nature of the particular compound of formula (I)which is being used. Enteric-coated and enteric-coated controlledrelease formulations are also within the scope of the invention.Suitable enteric coatings include cellulose acetate phthalate,polyvinylacetate phthalate, hydroxypropylmethylcellulose phthalate andanionic polymers of methacrylic acid and methacrylic acid methyl ester.Suitable enteric coated and enteric coated controlled releaseformulations include tablets and capsules.

Pharmaceutical compositions suitable for oral administration can bepresented in discrete units, such as capsules, cachets, lozenges, ortablets, each containing a predetermined amount of a compound of formula(I); as a powder or granules; as a solution or a suspension in anaqueous or non-aqueous liquid; or as an oil-in-water or water-in-oilemulsion. As indicated, such compositions can be prepared by anysuitable method of pharmacy which includes the step of bringing intoassociation the active compound and the carrier (which can constituteone or more accessory ingredients). In general, the compositions areprepared by uniformly and intimately admixing the active compound with aliquid or finely divided solid carrier, or both, and then, if necessary,shaping the product. For example, a tablet can be prepared bycompressing or moulding a powder or granules of the compound, optionallywith one or more accessory ingredients. Compressed tablets can beprepared by compressing, in a suitable machine, the compound in afree-flowing form, such as a powder or granules optionally mixed with abinder, lubricant, inert diluent and/or surface active/dispersingagent(s). Moulded tablets can be made by moulding, in a suitablemachine, the powdered compound moistened with an inert liquid diluent.Controlled release tablets can be prepared in similar manner and withthe addition of, for example, hydroxypropylmethyl cellulose.

Enteric-coated tablets can be prepared by coating the tablets with anenteric polymer such as cellulose acetate phthalate, polyvinylacetatephthalate, hydroxypropylmethyl-cellulose phthalate, or anionic polymersof methacrylic acid and methacrylic acid methyl ester (Eudragit L).Except for Eudragit L, these polymers should also include 10% (by weightof the quantity of polymer used) of a plasticizer to prevent membranecracking during application or on storage. Suitable plasticizers includediethyl phthalate, tributyl citrate and triacetin.

Enteric-coated controlled release tablets can be prepared by coatingcontrolled release tablets with an enteric polymer such as celluloseacetate phthalate, polyvinylacetate phthalate,hydroxypropylmethyl-cellulose phthalate, or anionic polymers ofmethacrylic acid and methacrylic acid methyl ester (Eudragit L). Exceptfor Eudragit L, these polymers should also include 10% (by weight of thequantity of polymer used) of a plasticizer to prevent membrane crackingduring application or on storage. Suitable plasticizers include diethylphthalate, tributyl citrate and triacetin.

Capsules can be prepared by admixing a compound of formula (I) with, forexample, magnesium stearate, pregelantinised starch, sodium starchglycollate, and/or magnesium stearate and filling two-part hard gelatincapsules with the resulting mixture.

Controlled release capsule compositions can be prepared by admixing acompound of formula (I) with, for example, microcrystalline celluloseand/or lactose, extruding using an extruder, then spheronising anddrying the extrudate. The dried pellets are coated with a releasecontrolling membrane, for example ethyl cellulose, and filled intotwo-part, hard gelatin capsules.

Enteric capsule compositions can be prepared by admixing a compound offormula (I) with, for example, microcrystalline cellulose and/orlactose, extruding using an extruder, then spheronising and drying theextrudate. The dried pellets are coated with an enteric membrane, forexample cellulose acetate phthalate containing a plasticizer, forexample diethyl phthalate and filled into two-part, hard gelatincapsules.

Pharmaceutical compositions suitable for buccal (sub-lingual)administration include lozenges comprising a compound of formula (I) ina flavored base, usually sucrose and acacia or tragacanth, and pastillescomprising the compound in an inert base such as gelatin and glycerin orsucrose and acacia.

Pharmaceutical compositions suitable for parenteral administrationconveniently comprise sterile aqueous preparations of a compound offormula (I), preferably isotonic with the blood of the intendedrecipient. These preparations are preferably administered intravenously,although administration can also be effected by means of subcutaneous,intramuscular, or intradermal injection. Such preparations canconveniently be prepared by admixing the compound with water andrendering the resulting solution sterile and isotonic with the blood.Injectable compositions according to the invention will generallycontain from 0.1 to 5% w/w of the active compound.

Pharmaceutical compositions suitable for rectal administration arepreferably presented as unit-dose suppositories. These can be preparedby admixing a compound of formula (I) with one or more conventionalsolid carriers, for example, cocoa butter, and then shaping theresulting mixture.

Transdermal administration is also possible. Pharmaceutical compositionssuitable for transdermal administration can be presented as discretepatches adapted to remain in intimate contact with the epidermis of therecipient for a prolonged period of time. Such patches suitably containthe active compound in an optionally buffered, aqueous solution,dissolved and/or dispersed in an adhesive, or dispersed in a polymer. Asuitable concentration of the active compound is about 1% to 35%,preferably about 3% to 15%. As one particular possibility, the activecompound can be delivered from the patch by electrotransport oriontophoresis, for example, as described in Pharmaceutical Research,3(6), 318 (1986).

The compounds of formula (I) can be prepared by conventional methodsknown to a skilled person or in an analogous manner to processesdescribed in the art. For example, compounds of formula (I) wherein R¹is H can be prepared from compounds of formula (II)

wherein R^(1a) is an alkyl moiety (e.g., C₁₋₄ alkyl, suitably methyl),by dealkylation with a suitable agent, such as boron tribromide, in asuitable organic solvent, for example methylene chloride.

According to a second process (B), a compound of formula (I) wherein R¹is methyl, or a salt, solvate, or physiologically functional derivativethereof, may be prepared from a compound of formula (III)

by oxidation of the sulfur group with, for example, a mixture of osmiumtetroxide and N-methyl-morpholine-N-oxide.

Compounds of formula (II) or (III) may be prepared from compounds offormula (IV), wherein R^(1a) is defined above, by methods known in theart, particularly those described in WO96/16051.

Compounds of formula (IV) can be prepared by methods described inWO96/16051 or by reacting compounds of formula (V) with compounds offormula (Va)

wherein Z is a suitable leaving group, for example, halo, by firstreacting the compound of formula (V) with a base, for example aqueouspotassium hydroxide at an elevated temperature, for example 100° C.,cooling, and then adding the compound of formula (Va).

Compounds of formula (V) can be prepared from compounds of formula (VI)

by reaction with ammonium thiocyanate and bromine in a suitable solventsuch as acetic acid.

Compounds of formula (VI) are commercially available or can be preparedby methods well known or readily available to those skilled in the art.

Compounds of formula (Va) can be prepared from compounds of formula(VII)

wherein R² is a suitable hydroxy protecting group, for example,tert-butyldimethylsilyl, by oxidation of the compound of formula (VII)with, for example, sodium periodate and ruthenium trichloride in asuitable solvent such as carbon tetrachloride/acetonitrile/water.Subsequent to the oxidation, the R² protected hydroxy is deprotected andconverted to the appropriate leaving group Z by known methods, forexample, with HBr.

Compounds of formula (VII) can be prepared from the corresponding diolsby methods well known or readily available to those skilled in the art.The diols are commercially available or can be prepared by methods wellknown or readily available to those skilled in the art.

The compounds of formula (I), substantially free of other opticalisomers can be obtained either by chiral synthesis, for example, by theuse of the appropriate chiral starting material(s), such as a chiralcompound of formula (Va), or by resolution of the products obtained fromachiral syntheses, for example, by chiral hplc, enzymatic resolution, orby classical resolution with chiral acids.

Optional conversion of a compound of formula (I), or a compound offormula (I) comprising a basic substituent, to a corresponding acidaddition salt may be effected by reaction with a solution of theappropriate acid, for example, one of those recited earlier. Optionalconversion of a compound of formula (I) comprising an acidic substituentto a corresponding base salt may be effected by reaction with a solutionof the appropriate base, for example, sodium hydroxide. Optionalconversion to a physiologically functional derivative, such as an ester,can be carried out by methods known to those skilled in the art orobtainable from the chemical literature.

In addition, compounds of the formula (I) may be converted to differentcompounds of the formula (I) by standard methods known or available fromthe literature to those skilled in the art, for example by methylationof a hydroxy group.

For a better understanding of the invention, the following Examples aregiven by way of illustration and are not to be construed in any way aslimiting the scope of the invention.

General Procedures: Proton magnetic resonance spectra were recorded at300 MHz. Mass spectra were recorded under atmospheric pressure chemicalionization (APCI) conditions on a LCMS instrument or were performed byOneida Research Services, Inc. under chemical ionization (CI) conditionsusing methane as the reagent gas. Elemental Analysis were performed byAtlantic Microlab, Inc. All reactions were performed under nitrogenatmosphere. TLC plates were Whatman MK6F silica gel 60 plates and werevisualized under a UV lamp. Column chromatography was performed with EMScience silica Gel 60 (230-400 mesh). Reagents were obtained fromAldrich Chemical Co. unless otherwise noted and were used withoutfurther purification. Solvents were Aldrich anhydrous grade.

EXAMPLE 1 Preparation of(3S)-2,3,4,5-Tetrahydro-3-ethyl-3-butyl-5-phenyl-7-chloro-8-methoxy-1,5-benzothiazepine-1,1-dioxideand(3S)-2,3,4,5-Tetrahydro-3-ethyl-3-butyl-5-phenyl-7-chloro-8-hydroxy-1,5-benzothiazepine-1,1-dioxide

(±)-2-((Tert-butyldimethylsilyl)oxy)methyl-ethyl-hexanol (1). To aslurry of 60% NaH (21.2 g) in 800 ml THF was added in 3 portions2-n-butyl-2-ethyl-1,3-propanediol (85.0 g) and stirred for 1 h. Themixture was cooled to 0° C. To the resulting gum was added a 1 Msolution of tert-butyldimethylsilyl chloride in THF (530 ml) and stirredovernight allowing the solution to warm to RT. The solvent wasevaporated and the residue was partitioned between water (400 ml) andether (300 ml). The ether layer was washed with bicarbonate solution andbrine and concentrated. Column chromatography (5% ethylacetate/petroleum ether) gave 1 as a colorless oil (142.6 g).

MS Da/e=275 (MH⁺).

Calcd for C₁₅H₃₄O₂Si: C, 65.63; H, 12.48. Found: C, 65.87; H, 12.47.

(±)-2-(Bromomethyl)-2-ethyl-hexanoic acid (2). To a solution of 1 (142.6g) in 300 ml CCl₄, 300 ml CH₃CN, and 450 ml H₂O at 0° C. was added NalO₄(283 g) and RuCl₃ (2.0 g) and stirred for 20 h allowing the reactionmixture to warm to RT. The reaction mixture was filtered through Celiteand the filtrate was concentrated by rotary evaporation. The residue wastransferred to a separatory funnel and partitioned between H₂O andCH₂Cl₂. The aqueous phase was extracted 3 times with CH₂Cl₂, dried,concentrated. The residue was taken up in 48% HBr (500 ml) and refluxedfor 24 h. After cooling to RT the solution was transferred to aseparatory funnel, extracted 3 times with ethyl ether, washed once withbrine, dried over Na₂SO₄, and concentrated. The product was purified bycolumn chromatography on silica gel eluting the product with 20% ethylacetate/petroleum ether giving 2 (111 g).

MS Da/e=157 (M−Br), 237, 239 (M+1).

Calcd for C₉H₁₇O₂Br: C, 45.59; H, 7.23; Br, 33.70. Found: C, 46.27; H,7.17; Br, 32.94.

2-Amino-5-chloro-6-methoxybenzothiazole (4). To a solution of3-chloro-p-anisidine (3, 58.4 g) in acetic acid (400 ml) was addedammonium thiocyanate and the mixture was stirred for 30 min at RT. Thereaction mixture was cooled to 15° C. in an ice bath. To the cooledreaction mixture was added a solution of bromine (17.2 ml) in aceticacid (200 ml) over 10 min. After 10 min stirring the reaction mixturewas allowed to warm to RT. After stirring at RT for 3.5 h, the reactionmixture was filtered and the solids caught on filter paper. The solidswere transferred to a flask and 200 ml water was added. The suspensionwas stirred vigorously and 30 ml 50% aqueous NaOH was added. The mixturewas filtered catching the product on filter paper. The powder was vacuumoven dried at 120° C. giving 4 (51.0 g)

MS Da/e=215 (M+1).

Calcd for C₈H₇N₂SOCl: C, 44.72; H, 3.29; N, 13.05; S,14.93. Found: C,44.63; H, 3.30; N, 12.96; S, 14.83.

(±)-2-(((2-Amino-4-chloro-5-methoxy-phenyl)thio)methyl)-2-ethylhexanoicacid (5). To a suspension of 4 (20.0 g) in H₂O (200 ml) was added KOH(100 g). The slurry was refluxed for 7 h and allowed to cool to RT. Tothe dark solution was added 2 (33.2 g) in one portion. The reactionmixture was stirred for 18 h at which point the pH was adjusted to 4with HCl. The mixture was transferred to a separatory funnel andextracted three times with ethyl acetate. The organic layer was driedand concentrated. The product was purified by column chromatography onsilica gel eluting the product with 10% ethyl acetate/petroleum ethergiving 5 (30.1 g).

MS Da/e=368 (M+Na).

(±)-2,3-Dihydro-3-ethyl-3-butyl-5-H-7-chloro-8-methoxy-1,5-benzothiazepine-4-one(6). To a suspension of 5 (72.0 g) in tetradecane (900 ml) was addedtoluene sulfonic acid (3.2 g). The mixture was heated to refluxtemperature and allowed to reflux for 15 min collecting 4 ml H₂O in aDean-Stark trap. The solution was allowed to cool and transferred to a 1liter erlenmeyer flask that was allowed to sit for 18 h at 4° C. Thetetradecane was decanted leaving solids that were recrystallized frommethanol/water. The mother liquors and the tetradecane solution wereapplied to a silica gel column and the remaining product eluted with 20%ethyl acetate/petroleum ether. The columned material was combined withthe recrystallized material giving 6 (52.6 g).

MS Da/e=350 (M+Na).

Calcd for C₁₆H₂₂NSO₂Cl: C, 58.61; H, 6.76; N, 4.27; S, 9.78. Found: C,58.70; H, 6.82; N, 4.23; S, 9.82.

(3R)-2,3-Dihydro-3-ethyl-3-butyl-5-H-7-chloro-8-methoxy-1,5-benzothiazepine-4-one(7). The racemic 6 (50 g) was resolved on a CHIRALPAK AD™ 10×50 cmcolumn eluting with 100% methanol at 25° C. The s isomer eluted first,and the r isomer eluted second. After concentrating down the secondpeak, isolated 7 (23.28 g, 99% ee).

¹H NMR (CDCl₃) d 7.82 (s, 1H), 7.03, (s, 1H), 6.99 (s, 1H), 3.88 (s,3H), 2.95 (s, 2H), 1.85-1.45 (m, 4H), 1.25 (m, 4H), 0.86 (m, 6H).

(3R)-2,3-Dihydro-3-ethyl-3-butyl-5-phenyl-7-chloro-8-methoxy-1,5-benzothiazepine-4-one(8). To a solution of 7 (10.0 g) in iodobenzene (75 ml) was added copper(I) iodide (0.30 g) and potassium carbonate (4.23 g). The mixture wasrefluxed for 5.5 h at which time it was allowed to cool to RT. Thereaction mixture was loaded directly onto a silica gel column. Theiodobenzene was eluted with petroleum ether, and the product was elutedwith 15% ethyl acetate/petroleum ether giving 8 (10.9 g).

MS Da/e=404 (M+1), 426 (M+Na).

Calcd for C₂₂H₂₆NSO₂Cl: C, 65.41; H, 6.49; N, 3.47; S,7.94. Found: C,65.15; H, 6.59; N, 3.34; S, 7.72.

(3S)-2,3,4,5-Tetrahydro-3-ethyl-3-butyl-5-phenyl-7-chloro-8-methoxy-1,5-benzothiazepine-1,1-dioxide(9). To a 1 M solution of lithium aluminum hydride in ethyl ether (91.5ml) was added dropwise at 0° C. a 7.2 M solution of sulfuric acid in THF(6.4 ml) and the mixture was stirred at 0° C. for 1 h. To the mixture at0° C. was added 8 (10.9 g) in THF (75 ml). The reaction mixture wasallowed to warm to RT and stirred for 3.5 h at RT at which point it wascooled back to 0° C. and a 30% (v/v) solution of H₂O in THF was addeddropwise. A 1 N solution of NaOH (15 ml) was added. The reaction mixturewas filtered through a sintered glass funnel to remove the aluminumoxides. The filtrate was transferred to a separatory funnel andpartitioned between water and ethyl ether. The aqueous layer wasextracted three times with ether. The organic phase was dried (Na₂SO₄)and concentrated. The resulting oil was taken up in THF (175 ml). To theTHF solution was added t-butanol (60 ml), N-methyl-morpholine-N-oxide(10.7 g) and osmium tetraoxide (2.5 wt % in t-butanol, 7.6 ml). Thereaction mixture was stirred for 18 h at RT. The reaction mixture wastransferred to a separatory funnel and partitioned between brine andethyl acetate. The aqueous layer was extracted three times with ethylacetate. The organic layer was dried, concentrated and the residueapplied to a silica gel column. The product was eluted with 10% ethylacetate/petroleum ether giving 9 (10.92 g).

m.p.=147.5° C.

MS Da/e=422 (M+1), 444 (M+Na).

Calcd for C₂₂H₂₈NSO₃Cl: C, 62.62; H, 6.69; N, 3.32; S,7.60. Found: C,62.53; H, 6.62; N, 3.32; S, 7.53.

(3S)-2,3,4,5-Tetrahydro-3-ethyl-3-butyl-5-phenyl-7-chloro-8-hydroxy-1,5-benzothiazepine-1,1-dioxide(Example 1). To a solution of 9 (10.92 g) in methylene chloride (150 ml)at 0° C. was added a 1 M solution of boron tribromide in methylenechloride (36.3 ml). The reaction mixture was allowed to slowly warm toRT and stirred for 18 h at which point it was cooled back to 0° C. andwater (100 ml) was added dropwise. The mixture was transferred to aseparatory funnel and extracted three times with methylene chloride. Theorganic extracts were dried, concentrated and the residue applied to asilica gel column. The product was eluted with 30% ethylacetate/petroleum ether giving Example 1 (10.12 g).

M.P.=179.6-180.2° C.

MS Da/e=406 (M−1, negative ion mode).

Calcd for C₂₁H₂₆NSO₃Cl: C, 61.83; H, 6.42; N, 3.43; S,7.86. Found: C,61.76; H, 6.47; N, 3.37; S, 7.76.

Biological Assay

(I) In vivo Inhibition of Bile Acid Reabsorption

Male Spraque-Dawley rats (CD, Charles River) weighing 220-260 gm werehoused in individual cages and fed normal chow. The rats were dosed byoral gavage (1 ml/100 gm body weight) with test compounds as asuspension in 0.5% methylcellulose at 9:00 a.m. and 3:30 p.m. for twodays. The control group received 0.5% methylcellose. Two hours after themorning dose on day two, the rats were given a trace amount (1.3 nmoles)of 23,25−⁷⁵Se-homocholic acid taurine (⁷⁵SeHCAT) in 1.0 ml salineorally. ⁷⁵SeHCAT, a synthetic gamma emitting bile acid analog which isabsorbed by the ileal bile acid active uptake system similar totaurocholic acid, has been used clinically as a measure of ileal bileacid absorption. Feces were collected over the 24 hours following⁷⁵SeHCAT administration. Fecal content of ⁷⁵SeHCAT was determined usinga Packard Auto-Gamma 5000 Series gamma-counter. The % inhibition of bileacid reabsorption is calculated as follows:${1\quad {minus}\frac{{{total}^{75}{SeHCAT}} - {{excreted}^{75}{SeHCAT}\quad {of}\quad {treated}}}{{{total}^{75}{SeHCAT}} - {{excreted}^{75}{SeHCAT}\quad {of}\quad {control}}} \times 100} = {\% \quad {inhibition}}$

The percent of inhibition of bile acid reabsorption in the rat using⁷⁵SeHCAT was used to determine the ED₃₀ (the dose required to give 30%inhibition of bile acid uptake).2,3,4,5-Tetrahydro-3-ethyl-3-butyl-5-phenyl-7-chloro-8-hydroxy-1,5-benzothiazepine-1,1-dioxide(Example 1 of the present invention), and the corresponding bromocompound,2,3,4,5-tetrahydro-3-ethyl-3-butyl-5-phenyl-7-bromo-8-hydroxy-1,5-benzothiazepine-1,1-dioxide,(Example A, as described in PCT/GB95/02700), were tested back-to-back intwo series of experiments with 6 rats in each set (n=12 total).

ED₃₀ (mg/kg) Example 1 0.048 Example A 0.17

(II) Percent Cholesterol Lowering in Rats

Hypercholesterolemia was induced in male Spraque-Dawley rats (CD,Charles River weighing 200-300 g) by administration of a diet enrichedin cholesterol and cholic acid. The diet was prepared from WayneLaboratory Lab Blocks ground into meal and mechanically mixed withpowdered cholesterol and cholic acid to a final concentration (byweight) of 1% and 0.5%, respectively. Prior to administration of thediet, blood was collected under halothane anesthesia by cardiac punctureto determine baseline lipid levels. Serum was obtained for analysis oftotal cholesterol (TC), high density lipoprotein cholesterol (HDL-C),and dextran-precipitable lipoprotein-cholesterol (VLDL+LDL). The ratswere divided into groups so that each group had similar baseline serumlipid levels. Five days following the initial sampling for serum lipidsthe rats were fed ab lib the cholesterol-cholic acid enriched diet andcompound administration was begun. The compound was administered bygavage as a suspension in 0.5% methylcellulose (1 ml/100 g body weight)b.i.d. at 9:00 a.m. and 3:00 p.m. for 3 days and at 9:00 a.m. on dayfour. Control animals received 0.5% methylcellulose only. The rats werebleed four hours after the last dose for the determination of serumlipids. All blood collections were done after a 4-h fast. Serum TCconcentrations were determined enzymatically using reagents obtainedfrom Seragen Diagnostics (2). Serum HDL-C was determined after selectiveprecipitation of VLDL and LDL with dextran sulfate and magnesiumsulfate, with reagents from Seragen (3). HDL-C was determined in thesupernatant. VLDL+LDL cholesterol was determined as the differencebetween total and HDL-C. The following results were obtained for Example1 and Example A, as defined above.

Dose (mg/kg) 0.3 0.1 0.03 Example 1 81% 56% 48% Example A 53% 17% 14%

The results clearly demonstrate the unexpectedly improvedcholesterol-lowering properties of the compounds of the presentinvention.

Pharmaceutical Composition Examples

In the following Examples, the active compound can be any compound offormula (I) and/or a pharmaceutically acceptable salt, solvate, orphysiologically functional derivative thereof.

(I) Tablet Compositions

The following compositions A and B can be prepared by wet granulation ofingredients (a) to (c) and (a) to (d) with a solution of povidone,followed by addition of the magnesium stearate and compression.

mg/tablet mg/tablet Composition A (a) Active ingredient 250 250 (b)Lactose B.P. 210 26 (c) Sodium Starch Glycollate 20 12 (d) Povidone B.P.15 9 (e) Magnesium Stearate 5 3 500 300 Composition B (a) Activeingredient 250 250 (b) Lactose 150 150 — (c) Avicel PH 101 60 26 (d)Sodium Starch Glycollate 20 12 (e) Povidone B.P. 15 9 (f) MagnesiumStearate 5 3 500 300 Composition C Active ingredient 100 Lactose 200Starch 50 Povidone 5 Magnesium Stearate 4 359

The following compositions D and E can be prepared by direct compressionof the admixed ingredients. The lactose used in composition E is of thedirect compression type.

mg/tablet Composition D Active ingredient 250 Magnesium Stearate 4Pregelatinised Starch NF15 146 400 Composition E Active ingredient 250Magnesium Stearate 5 Lactose 145 Avicel 100 500 Composition F(Controlled release composition) (a) Active ingredient 500 (b)Hydroxypropylmethylcellulose 112 Methocel K4M Premium) (c) Lactose B.P.53 (d) Povidone B.P.C. 28 (e) Magnesium Stearate 7 700

The composition can be prepared by wet granulation of ingredients (a) to(c) with a solution of povidone, followed by addition of the magnesiumstearate and compression.

Composition G (Enteric-coated Tablet)

Enteric-coated tablets of Composition C can be prepared by coating thetablets with 25 mg tablet of an enteric polymer such as celluloseacetate phthalate, polyvinylacetate phthalate,hydroxypropylmethyl-cellulose phthalate, or anionic polymers ofmethacrylic acid and methacrylic acid methyl ester (Eudragit L). Exceptfor Eudragit L, these polymers should also include 10% (by weight of thequantity of polymer used) of a plasticizer to prevent membrane crackingduring application or on storage. Suitable plasticizers include diethylphthalate, tributyl citrate and triacetin.

Composition H (Enteric-coated Controlled Release Tablet)

Enteric-coated tablets of Composition F can be prepared by coating thetablets with 50 mg/tablet of an enteric polymer such as celluloseacetate phthalate, polyvinylacetate phthalate,hydroxypropylmethyl-cellulose phthalate, or anionic polymers ofmethacrylic acid and methacrylic acid methyl ester (Eudragit L). Exceptfor Eudragit L, these polymers should also include 10% (by weight of thequantity of polymer used) of a plasticizer to prevent membrane crackingduring application or on storage. Suitable plasticizers include diethylphthalate, tributyl citrate and triacetin.

(II) Capsule Compositions

Composition A

Capsules can be prepared by admixing the ingredients of Composition Dabove and filling two-part hard gelatin capsules with the resultingmixture. Composition B (infra) may be prepared in a similar manner.

mg/capsule Composition B (a) Active ingredient 250 (b) Lactose B.P. 143(c) Sodium Starch Glycollate 25 (d) Magnesium Stearate 2 420 CompositionC (a) Active ingredient 250 (b) Macrogol 4000 BP 350 600

Capsules can be prepared by melting the Macrogol 4000 BP, dispersing theactive ingredient in the melt and filling two-part hard gelatin capsulestherewith.

mg/capsule Composition D Active ingredient 250 Lecithin 100 Arachis Oil100 450

Capsules can be prepared by dispersing the active ingredient in thelecithin and arachis oil and filling soft, elastic gelatin capsules withthe dispersion.

mg/capsule Composition E (Controlled release capsule) (a) Activeingredient 250 (b) Microcrystalline Cellulose 125 (c) Lactose BP 125 (d)Ethyl Cellulose 13 513

The controlled release capsule composition can be prepared by extrudingmixed ingredients (a) to (c) using an extruder, then spheronising anddrying the extrudate. The dried pellets are coated with a releasecontrolling membrane (d) and filled into two-part, hard gelatincapsules.

mg/capsule Composition F (Enteric capsule) (a) Active ingredient 250 (b)Microcrystalline Cellulose 125 (c) Lactose BP 125 (d) Cellulose AcetatePhthalate 50 (e) Diethyl Phthalate 5 555

The enteric capsule composition can be prepared by extruding mixedingredients (a) to (c) using an extruder, then spheronising and dryingthe extrudate. The dried pellets are coated with an enteric membrane (d)containing a plasticizer (e) and filled into two-part, hard gelatincapsules.

Composition G (Enteric-coated Controlled Release Capsule)

Enteric capsules of Composition E can be prepared by coating thecontrolled-release pellets with 50 mg/capsule of an enteric polymer suchas cellulose acetate phthalate, polyvinylacetate phthalate,hydroxypropylmethylcellulose phthalate, or anionic polymers ofmethacrylic acid and methacrylic acid methyl ester (Eudragit L). Exceptfor Eudragit L, these polymers should also include 10% (by weight of thequantity of polymer used) of a plasticizer to prevent membrane crackingduring application or on storage. Suitable plasticizers include diethylphthalate, tributyl citrate and triacetin.

(III) Intravenous injection composition Active ingredient 0.200 gSterile, pyrogen-free phosphate buffer (pH 9.0) to 10 ml

The active ingredient is dissolved in most of the phosphate buffer at35-40° C., then made up to volume and filtered through a sterilemicropore filter into sterile 10 ml glass vials (Type 1) which aresealed with sterile closures and overseals.

(IV) Intramuscular injection composition Active ingredient 0.20 g BenzylAlcohol 0.10 g Glycofurol 75 1.45 g Water for Injection q.s. to 3.00 ml

The active ingredient is dissolved in the glycofurol. The benzyl alcoholis then added and dissolved, and water added to 3 ml. The mixture isthen filtered through a sterile micropore filter and sealed in sterile 3ml glass vials (Type 1).

(V) Syrup composition Active ingredient  0.25 g Sorbitol Solution  1.50g Glycerol  1.00 g Sodium Benzoate  0.005 g Flavour 0.0125 ml PurifiedWater q.s. to   5.0 ml

The sodium benzoate is dissolved in a portion of the purified water andthe sorbitol solution added. The active ingredient is added anddissolved. The resulting solution is mixed with the glycerol and thenmade up to the required volume with the purified water.

(VI) Suppository composition mg/suppository Active ingredient 250 HardFat, BP (Witepsol H15 - Dynamit NoBel) 1770 2020

One-fifth of the Witepsol H15 is melted in a steam-jacketed pan at 45°C. maximum. The active ingredient is sifted through a 200 lm sieve andadded to the molten base with mixing, using a Silverson fitted with acutting head, until a smooth dispersion is achieved. Maintaining themixture at 45° C., the remaining Witepsol H15 is added to the suspensionwhich is stirred to ensure a homogenous mix. The entire suspension isthen passed through a 250 lm stainless steel screen and, with continuousstirring, allowed to cool to 40° C. At a temperature of 38-40° C., 2.02g aliquots of the mixture are filled into suitable plastic moulds andthe suppositories allowed to cool to room temperature.

(VII) Pessary composition mg/pessary Active ingredient (63 lm) 250Anhydrous Dextrose 380 Potato Starch 363 Magnesium Stearate 7 1000

The above ingredients are mixed directly and pessaries prepared bycompression of the resulting mixture.

(VIII) Transdermal composition Active ingredient  200 mg Alcohol USP 0.1 ml Hydroxyethyl cellulose

The active ingredient and alcohol USP are gelled with hydroxyethylcellulose and packed in a transdermal device with a surface area of 10cm².

What is claimed is:
 1. A compound of formula (I)

wherein R¹ is H or methyl, or a salt or solvate thereof.
 2. A compoundselected from the group consisting of:(±)-2,3,4,5-Tetrahydro-3-ethyl-3-butyl-5-phenyl-7-chloro-8-hydroxy-1,5-benzothiazepine-1,1-dioxide;(3S)-2,3,4,5-Tetrahydro-3-ethyl-3-butyl-5-phenyl-7-chloro-8-hydroxy-1,5-benzothiazepine-1,1-dioxide;and(±)-2,3,4,5-Tetrahydro-3-ethyl-3-butyl-5-phenyl-7-chloro-8-methoxy-1,5-benzothiazepine-1,1-dioxideand salts and solvates thereof.
 3. A compound selected from the groupconsisting of(+)-2,3,4,5-tetrahydro-3-ethyl-3-butyl-5-phenyl-7-chloro-8-hydroxy-1,5-benzothiazepine-1,1-dioxide,a salt of(±)-2,3,4,5-tetrahydro-3-ethyl-3-butyl-5-phenyl-7-chloro-8-hydroxy-1,5-benzothiazepine-1,1-dioxide,and a solvate of(±)-2,3,4,5-tetrahydro-3-ethyl-3-butyl-5-phenyl-7-chloro-8-hydroxy-1,5-benzothiazepine-1,1-dioxide.4. A compound selected from the group consisting of(3S)-2,3,4,5-tetrahydro-3-ethyl-3-butyl-5-phenyl-7-chloro-8-hydroxy-1,5-benzothiazepine-1,1-dioxide,a salt of(3S)-2,3,4,5-tetrahydro-3-ethyl-3-butyl-5-phenyl-7-chloro-8-hydroxy-1,5-benzothiazepine-1,1-dioxide,and a solvate of(3S)-2,3,4,5-tetrahydro-3-ethyl-3-butyl-5-phenyl-7-chloro-8-hydroxy-1,5-benzothiazepine-1,1-dioxide.5. A process for the manufacture of a compound according to claim 1,wherein R¹ is hydrogen, which comprises: dealkylation of a compound offormula (II)

 wherein R^(1a) is an alkyl moiety.
 6. A process for the manufacture ofa compound according to claim 1, wherein R¹ is methyl, which comprisesoxidising a compound of formula (III)


7. A pharmaceutical composition comprising a compound according toclaim
 1. 8. The pharmaceutical composition according to claim 7, furthercomprising an acceptable carrier.
 9. The pharmaceutical compositionaccording to claim 7, further comprising a physiologically active agentselected from the group consisting of bile acid sequestering agents,fibric acid derivatives, and HMG-CoA reductase inhibitors.
 10. A methodof prophylaxis or treating a hyperlipidemic condition in a mammalcomprising administration of a therapeutically effective amount of acompound according to claim
 1. 11. A method of treating atherosclerosiscomprising administering a therapeutically effective amount of acompound according to claim
 1. 12. A method of inhibiting the absorptionof bile acids from the intestine of a mammal comprising administering aneffective bile acid inhibiting amount of a compound according toclaim
 1. 13. A method of reducing the blood plasma or serumconcentrations of LDL cholesterol in a mammal comprising administering atherapeutically effective amount of a compound according to claim 1.